BIO Comments on Draft Guidance for Industry and Investigators on Safety Reporting Requirements for Investigational New Drug Applications and Bioavailability/Bioequivalence Studies

Re: Docket No. FDA-2010-D-0482-0001: Draft Guidance for Industry and Investigators on Safety Reporting Requirements for Investigational New Drug Applications and Bioavailability/Bioequivalence Studies

Dear Sir/Madam:

The Biotechnology Industry Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments on the Draft Guidance for Industry and Investigators on Safety Reporting Requirements for Investigational New Drug Applications and Bioavailability/Bioequivalence Studies. BIO finds the Draft Guidance helpful in clarifying FDA’s expectations with respect to the new Investigational New Drug (IND) safety requirements. The Agency has clearly stated its intention is to receive fewer, but higher quality IND safety reports and BIO supports the goal of ensuring that safety reports submitted during clinical trials are as useful and informative as possible. However, BIO is concerned that while the Draft Guidance and the accompanying Final Rule may internationally harmonize standard definitions for safety reporting, the requirements establish differing standards for assessing the causality between a drug exposure and a suspected adverse event and may in fact lead to divergence in reporting practices between international regions. In order to maximize compliance and reduce the risk of underreporting, we request additional clarification in the Draft Guidance on this question and ask that FDA coordinate with other international regulatory authorities in the spirit of global harmonization to develop a common approach to causality assessment.

BIO represents more than 1,100 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products, thereby expanding the boundaries of science to benefit humanity by providing better healthcare, enhanced agriculture, and a cleaner and safer environment.


I. Lack of Harmonization will result in Different Safety Information being Reported in Different Regions

BIO appreciates and welcomes FDA’s overall effort to harmonize the definitions of adverse reaction and suspected adverse reaction with those of the International Conference on Harmonization’s (ICH) guidelines on Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (ICH E2A). However, we are concerned that there are clear differences in how FDA and international health authorities interpret these terms in practice, particularly as they relate to a Sponsor’s assessment of causality between a drug exposure and an adverse event.

The Draft Guidance states “that Sponsors are to report to FDA only if there is evidence to suggest a causal relationship between the drug and the adverse event…” (lines 263-264) and that “although the investigator’s view of the causal relationship between an adverse event and the investigational drug is important, FDA believes that the Sponsor is better positioned than the individual investigator to assess the overall safety of the investigational drug because the Sponsor has access to serious adverse event reports from multiple study sites and is able to aggregate and analyze these reports.” (Lines 569-573)

These sections imply that if an investigator reports a serious adverse event (SAE) as possibly related to study treatment, the Sponsor is ultimately responsible for deciding whether the adverse event meets the definition of a “suspected adverse reaction” for regulatory reporting purposes. Consequently, a Sponsor could decide not to report a potential suspected, unexpected serious adverse event because it disagrees with the causal attribution of the investigator, due to the Sponsor being “better positioned”.

The view that a Sponsor may downgrade an investigator’s causality assessment represents a significant departure from the current international standard and BIO is concerned that these provisions may lead to divergence of international safety reporting practices. For example, the international standard (or requirement in some regions) for safety reporting from interventional studies is that the most conservative causality assessment be used to determine regulatory reporting requirements. For example, the United Kingdom’s Medicines and Healthcare products Regulatory Agency’s (MHRA) Good Pharmacovigilance Practice Guide explicitly states that marketing authorization holders should use the most conservative assessment for expediting purposes when the investigator and Sponsor do not agree on causality for an individual event report. This would preclude the Sponsor from over-riding an investigator’s assignment of positive attribution, an action the FDA’s Draft Guidance deems as acceptable. In addition, the MHRA Guide specifies that if a case initially has insufficient data to make an assessment, or if the investigator does not supply a causality assessment, the Sponsor should consider the event to be causally related.

The Draft Guidance also provides examples (lines 54-59) of serious adverse experiences that should not be reported to FDA under the guidance. We believe that those serious adverse experiences will continue to be reported in other regions, because neither the European Union (E.U.) nor Japan have indicated that such events, particularly if considered as possibly related by the investigator, would not meet the criteria for reporting.

Consequently, to meet the requirements of U.S., European and other regulators, a single adverse event report could face opposing causality assessments and health authority reporting paradigms. This in turn would lead to divergent approaches toward the production of annual safety reports, study reports and notification of new safety issues to investigators. Given that many IND trials have sites in both the E.U. and the U.S., this approach to causality assessments will result in different safety information being provided to regulatory authorities, ethics committees, Institutional Review Boards (IRBs), and investigators in the different regions. While BIO appreciates FDA’s intent to rationalize and decrease the number of meaningless IND safety reports, the Agency should be aware that multi-national Sponsors will now face both philosophical and operational challenges in an effort to meet the differing regulatory expectations of health authorities.

As such, BIO requests further clarification on the issue of how to address causality assessments, specifically in the context of whether to use the investigator's or the Sponsor's assessment of causality, in the event that the two differ. Additionally, we would appreciate FDA reaching out to its ICH partners to develop a common approach in the spirit of global harmonization.

If FDA maintains the view that the Sponsor is better positioned to assess causality of an adverse event and that it may be appropriate and even encouraged in certain situations where the Sponsor and investigator do not concur on causality, then we request that FDA please provide examples in the Final Guidance document when it may be appropriate for a Sponsor to downgrade an investigator’s causality assessment. For example, where the Sponsor’s assessment is that an event was most probably caused by the underlying disease and not by the investigational drug, but the investigator has stated in the report that the event is causally related to the drug, please describe the circumstances under which it would be appropriate for the Sponsor to make a downgraded causality assessment and not expedite the report to the FDA.

BIO also suggests that FDA further clarify what is expected of investigators when reporting adverse events and further discuss the topic of Investigator Good Adverse Event Reporting Practices in future guidance.

II. Data from ongoing Clinical Trials should not be Unblinded for the Purpose of Completing Aggregate Analyses of Serious Adverse Events

BIO also requests additional clarification regarding the unblinding of ongoing clinical trials. For example, the Draft Guidance states “At appropriate intervals, the numbers of such events in each arm of a controlled study should be compared and reported to FDA expeditiously as an IND safety report if there is an imbalance between arms suggesting there is a reasonable possibility that the drug caused the adverse event.” (Lines 339-343) Further, the Draft Guidance states “The Sponsor or an independent group should monitor the identified events during the course of the trial and submit an IND safety report if an aggregate analysis indicates that the events are occurring more frequently in the drug treatment group.” (Lines 365-369)

We believe the above text regarding the need to conduct analyses could be easily misinterpreted as requiring Sponsors or an independent body to unblind trial data. While we understand that this language is largely reflected in the ICH E2F Development Safety Update Report (DSUR) Guideline, we note that the current ICH E2F guideline includes the following language:

“Sponsors should not unblind data for the specific purpose of preparing the DSUR.” (See ICH E2F; Section 3.7, third paragraph, last sentence; page 11).

As such, we recommend that FDA include the following text in the Final Guidance:

“Sponsors should not be unblinded to clinical trial data from an ongoing trial for the purpose of completing aggregate analyses of serious adverse events, unless pre-specified by the statistical plan.”

The above text should be inserted in Line 343 after the conclusion of the sentence ending in “…event.” and in Line 369 at the conclusion of the sentence ending in “…section V.A.3.c]."”

We also are concerned that the Draft Guidance does not clarify under what circumstances Sponsors would be required to perform the comparisons of serious adverse events in different arms of the same study. The guidance should describe how often this type of compared group analysis should occur and what should trigger the analysis. For example, the guidance could state that Sponsors are responsible for noting the frequencies of serious adverse events being reported in a trial and should initiate a compared group analysis, probably through a Data Monitoring Committee (DMC), in cases where the overall incidence seems much higher than anticipated.

We believe this will ensure a better understanding of FDA's intent for the review of serious adverse events that are not study endpoints as well as serious events that are pre-specified in study protocols. Further, it will better harmonize FDA requirements with those of other regulatory health authorities that have adopted ICH E2F guidelines, which is one of the stated goals of FDA's current Draft Guidance (See Section II, p.1).


BIO appreciates this opportunity to comment on the Draft Guidance for Industry and Investigators on Safety Reporting Requirements for Investigational New Drug Applications and Bioavailability/Bioequivalence Studies. More specific, line-by-line comments are included in the following chart. We would be pleased to provide further input or clarification of our comments, as needed.


Andrew J. Emmett
Managing Director, Science and Regulatory Affairs
Biotechnology Industry Organization (BIO)